Patients with elevated tumor-infiltrating lymphocytes do better without additional Herceptin

Action Points

Note that this retropsective analysis of a clinical trial revealed that women with HER-2 positive breast cancer did not benefit from adjuvant Herceptin in the presence of stromal tumor-infiltrating lymphocytes.

Be aware that these findings run counter to a prior study that found essentially the opposite relationship.

Prognosis for human epidermal growth factor receptor 2 (HER2)-positive patients with lymphocyte-predominant breast cancer (LPBC) was significantly better following treatment with chemotherapy alone than it was for their counterparts receiving chemotherapy plus trastuzumab (Herceptin), an exploratory analysis of the North Central Cancer Treatment Group-N9831 trial has shown.

Among 489 patients from the N9831 trial receiving chemotherapy alone, 10-year Kaplan-Meier estimates for recurrence-free survival (RFS) among participants with high-levels of stromal tumor-infiltrating lymphocytes (STILs) was 90.9% compared with 64.5% for patients with low-levels of STILs.

In dramatic contrast, 10-year estimates for RFS among 456 patients who received the same chemotherapy regimen followed by weekly paclitaxel plus trastuzumab followed by trastuzumab alone were virtually identical in patients with high- and low-levels of STILs at 80% and 80.1%, respectively (HR 1.26; 95% CI 0.50-3.17; P=0.63).

Adjusted for important prognostic variables including age, nodal status, hormone receptor status, tumor grade, and size, lymphocyte predominant breast cancer status was still significantly associated with 81% improvement in RFS in the chemotherapy alone arm at a hazard ratio of 0.19 (95% CI 0.06-0.61; P=0.005) but not in the arm in which trastuzumab was given at a HR of 1.01 (95% CI 0.39-2.60; P=0.98).

Hormone receptor status was also associated with a significant 37% improvement in RFS in the chemotherapy arm (HR 0.63, 95% CI 0.42-0.94; P=0.02) but not in the arm that contained additional trastuzumab (HR 0.75; 95% CI 0.43-1.32; P=0.32).

"Analysis of HER2-positive cancers from patients enrolled in the FinHER adjuvant study has suggested that the levels of STILs are predictive of benefit from adjuvant trastuzumab therapy," Edith Perez, MD, Mayo Clinic, Jacksonville, Florida and colleagues write in JAMA Oncology.

"The goal of the present study was to determine whether the data from FinHER could be validated in a larger adjuvant trial with the standard 1 year of trastuzumab therapy such as N9831 [and] our findings do not show that increased levels of STILs, either assessed in deciles or dichotomously (LPBC; ≥60% STILs) were predictive of increased benefit from adjuvant trastuzumab but rather that patients with high levels of STILs (LPBC; ≥60% STILs) did not benefit from the additional of trastuzumab."

A total of 2,027 patients were enrolled in N9831 and a subset of 945 patients was included in the STILs analysis.

Patients had a median follow–up of 4.4 years (0 - 13.6 years).

"There were 162 disease recurrence events: 8 events in the LPBC group and 154 in the non-LPBC group," investigators observed.

Patients without recurrent disease were observed for a median of 6.9 years.

Patients with LPBC tumors did not derive any additional benefit from the addition of trastuzumab (HR 2.43, 95% CI 0.58-10.22; P=0.22).

Even if results showed that patients with high levels of STILs (LPBC; ≥60% STILs) did not benefit from the addition of trastuzumab, the authors caution that only 94 patients were classified as having LPBC and there were only eight disease recurrent events among this group.

"This means that this study was likely underpowered to detect a treatment effect in this group," Perez and colleagues caution.

In an accompanying editorial, Sylvia Adams, MD, New York University School of Medicine, New York, points out that in triple negative breast cancer, results have consistently shown that increased tumor-infiltrating lymphocytes (TIL) at baseline are associated with reduced recurrence rates and an improved survival in women with early breast cancer receiving adjuvant chemotherapy.

This includes the Finland Herceptin (FinHER) trial in which Loi et al (Ann Oncol 2014; 25:1544-50) point out that they had 1,010 early-stage breast cancer patients, the majority of whom were HER2-negative but among the HER2-positive patients, some 232 were randomized to nine weeks of trastuzumab or no trastuzumab in addition to chemotherapy.

At the same time, in the HER2-positive subset of patients, each 10% increase in lymphocytic infiltration was also significantly associated with decreased distant recurrence in patients randomized to trastuzumab.

Indeed, FinHER trial investigators concluded that their findings further support the idea that high levels of TILs should be considered as both a robust prognostic factor in triple negative disease as well as a signal of increased trastuzumab benefit in HER2-positive disease.

As Adams suggested, the difference between findings from the FinHER study regarding the benefit of trastuzumab in HER2-positive patients and its lack of benefit in the same group of patients in the current study may be traced back to hormone receptor status.

In the Perez et al study, hormone receptor status was an independent predictive factor with improved RFS in patients with HR-positive tumors compared with those with HR-negative tumors although again only in the chemotherapy group and not in the chemotherapy/trastuzumab group.

Fewer patients, about half, had HR-positive disease in the N9831 trial compared to almost three-quarters of the FinHER cohort.

There were also important differences in the tumor grade between the two trials although not nodal status.